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Page 2 of 14 Orekhov et al. Vessel Plus 2019;3:3 I http://dx.doi.org/10.20517/2574-1209.2018.80

changes to the advanced plaque, atherosclerotic lesion is characterized by the deposition of intracellular
[1,2]
lipids (mainly cholesteryl esters) in arterial sub-endothelial cells .

Generally, the foam cell formation is the result of interaction of cells with pro-atherogenic low-density
lipoprotein (LDL) providing cholesterol delivery and anti-atherogenic high-density lipoprotein (HDL)
providing its efflux. Foam cell formation through the very LDL receptor by remnant lipoprotein and
[3]
lipoprotein(a) and through other ways has also been described. However, the main source of fat in the
[4]
foam cells is plasma LDL . In this review, we discuss possible mechanisms of foam cell formation and
the role of intracellular lipid deposition as a trigger of atherosclerotic lesion development. In addition, the
objective of the review is to discuss current approaches to preventing the accumulation of lipids in arterial
cells because there is a general consensus that inhibition of foam cell formation is an important strategy for
preventing atherosclerosis.

MECHANISMS OF FOAM CELL FORMATION
The obvious close connection of atherosclerosis with foam cells led to the idea that lipid accumulation
is a necessary condition or fundamental even of atherogenesis. The origin of foam cells is still a matter
of controversy. Currently, the dominant view is that foam cells have an exclusively macrophage origin.
However, in the sub-endothelial intima of human arteries, macrophages represent a minority in comparison
with smooth muscle α-actin-positive cells (SMA+) that are typical smooth muscle cells and pericytes,
[5]
however, even in the initial lesions, almost all cells contain lipid inclusions . Consequently, not all cells
loaded with lipids are macrophages. According to the most recent data, in human coronary lesions, the
[6]
proportion of smooth muscle cells is higher than 50% of total number of foam cells . Nevertheless,
the culture of macrophages is widely used to study the mechanisms of foam cell formation, since the
macrophage is a simple and convenient model. Taking into account the possible role of LDL in the
accumulation of intracellular cholesterol, many research groups have attempted to induce the increase of
cholesterol level in cultured cells by incubation with lipoprotein.

Modified LDL
[7,8]
In hyperlipidemia at high LDL levels, fluid-phase pinocytosis induces foam cell formation . However,
generally native LDL does not cause lipid storage in cell cultures [5,9,10] . On the other hand, considerable lipid
accumulation was detected in the case of chemically modified LDL (acetylated, maleylated, succinylated,
oxidized, etc.) or treatment with formaldehyde, malondialdehyde, phospholipase A2, C and D, etc. [10,11] .
Therefore, chemically modified LDL is able to trigger foam cell formation, hence it is atherogenic. This
discovery initiated the search for a naturally occurring atherogenic modified LDL. Proceeding from the
hypothesis of oxidative modification, it was the oxidized LDL that was searched for but it was not found in
the blood, although some indirect signs of oxidation of circulating LDL were detected by detecting a marker
for evaluating the LDL oxidation in vivo [9,10] . A more reasonable way to detect the in vivo modified LDL, i.e.,
LDL particles capable of triggering lipid accumulation in cultured cells, was to search for such an atherogenic
lipoprotein circulating in patients with atherosclerosis. In addition to oxidation, other forms of atherogenic
modified LDL were discovered in the blood. Different groups at different times have found small dense LDL
(sdLDL), electronegative or LDL(-), and desialylated lipoprotein particles circulating in the blood [9,10] .

It was found that LDL(-), sdLDL and desialylated LDL particles have many common characteristics and can
all be oxidized [5,9,10] [Table 1]. This led to the idea that all known forms of atherogenic modification of LDL
can be present in the same lipoprotein particle, that is, there is multiple modification of LDL. In the blood,
the same multiply modified LDL particles possess the properties of small dense, electro-negative, oxidized
and desialylated lipoproteins [5,9,10] .

A mechanism of LDL multiple modification was proposed [Figure 1]. The hypothesis was tested under
conditions imitating the situation in vivo. Native (unmodified) LDL particles were isolated from circulation